In-silico Identification of Candidate Inhibitory Ligands against Ornithine Decarboxylase Enzyme for Human Sleeping Sickness Causing Trypanosoma bruceiHukkeri S1* and Alinne Batista Ambrosio2
- *Corresponding Author:
- Hukkeri S
Plant Science Department, McGill University
MacDonald Campus 21, 111 Lakeshore Road
Sainte Anne De-bellevue H9X3B9
Tel: +1 (438) 868-9732
E-mail: [email protected]
Received date: January 28, 2017; Accepted date: February 9, 2017; Published date: February 16, 2017
Citation: Hukkeri S, Ambrosio AB (2017) In-silico Identification of Candidate Inhibitory Ligands against Ornithine Decarboxylase Enzyme for Human Sleeping Sickness Causing Trypanosoma brucei. J Biomol Res Ther 6:148. doi: 10.4172/2167-7956.1000148
Copyright: © 2017 Hukkeri S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Ornithine Decarboxylase (ODC) catalyzes the decarboxylation of ornithine to putrescine. This is known to be a crucial step in the biosynthesis of polyamines. These polyamines are necessary for microbial cell growth and proliferation. Hence, ODC enzyme is the best target to treat African sleeping sickness disease-causing protozoan parasite, Trypanosoma brucei. ODC is a 5'-pyridoxal phosphate (PLP) dependent, an obligate homodimer enzyme with two identical active sites at the dimer interface, comprising the beta or alpha barrel domain from one subunit and beta-sheet domain from the other subunit. The catalytic residues are contributed to the active site from both monomers. An X-ray crystallography study on ODC in the wild T. brucei has revealed two structural changes upon ligand binding; an amino acid residue specifically Lys-69 is displaced by putrescine forming a new interaction and a side chain of Cys-360 moves to the active site. Mutation of the Cys residue to Ala or Ser amino acid reduces the Kcat energy of the decarboxylation reaction drastically. Interestingly, ligand ZINC01703953 shown interaction with ODC protein, Lys-69 functional amino acid with docked score of -8.28 out of 35 ligands tested based on Virtual Screening (VS) with AutoDock suite in the current study. Another, top scoring (-9.69) ligand, ZINC67855534 is found to interact with amino acid residues, involved in the active site formation of the ODC enzyme from our current VS experiment. Hence, the ligands ZINC01703953 and ZINC67855534 could possibly consider as potential candidates against T. brucei upon further in-vitro experimental validations.